Single-molecule force spectroscopy study of the effect of cigarette carcinogens on thrombomodulin–thrombin interaction  

作　　者：Jianli Liu Xuejie Zhang Xiaofeng Wang Li Xu Jingyuan Li Xiaohong Fang 

机构地区：[1]Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy ofSciences, Beijing 100190, China [2]Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academyof Sciences, Beijing 100049, China

出　　处：《Science Bulletin》2016年第15期1187-1194,共8页科学通报（英文版）

基　　金：supported by the National Basic Research Program of China (2013CB933701, 2013CB933704);the National Natural Science Foundation of China (21127901)

摘　　要：Exposure to cigarette smoke is a major risk factor for cancer and cardiovascular disease. Thrombosis is regarded as the main reason for smoking-related car- diovascular disease. However, the detail mechanism of how smoking promotes thrombosis is not fully under- stood. In this work, we investigated the impacts of one major cigarette carcinogens 4-（methylnitrosamino）-l-（3- pyridyl）-l-butanone （NNK） as well as its metabolite 4-（methylnitrosamino）- 1-（3-pyridyl）- 1-butanol （NNAL） on a key process in thrombosis regulation： thrombin- thrombomodulin （TM） binding. Atomic force microscopy based single-molecule force spectroscopy was applied to measure both in vitro and in vivo binding force of thrombin to TM in the absence and presence of NNK and NNAL respectively. The results revealed that NNK and NNAL can reduce the binding probability of TM and thrombin. The inhibition effect and underlying mechanism was further studied by molecular simulation. As indicated by our results, the cigarette carcinogens could cause a higher risk of thrombosis through the disruption of TM- thrombin interaction.Exposure to cigarette smoke is a major risk factor for cancer and cardiovascular disease. Thrombosis is regarded as the main reason for smoking-related cardiovascular disease. However, the detail mechanism of how smoking promotes thrombosis is not fully understood. In this work, we investigated the impacts of one major cigarette carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK) as well as its metabolite4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol(NNAL)on a key process in thrombosis regulation: thrombin–thrombomodulin(TM) binding. Atomic force microscopy based single-molecule force spectroscopy was applied to measure both in vitro and in vivo binding force of thrombin to TM in the absence and presence of NNK and NNAL respectively. The results revealed that NNK and NNAL can reduce the binding probability of TM and thrombin. The inhibition effect and underlying mechanism was further studied by molecular simulation. As indicated by our results, the cigarette carcinogens could cause a higher risk of thrombosis through the disruption of TM–thrombin interaction.

关 键 词：Cigarette carcinogens THROMBIN THROMBOMODULIN AFM Single-molecule forcespectroscopy Molecular simulation 

分 类 号：TS411[农业科学—烟草工业] R54[医药卫生—心血管疾病]